Substituted (thiazol-2-yl)-amide or sulfonamide as glycokinase activators useful in the treatment of type 2 diabetes

ABSTRACT

Compounds of the formula 
 
R—NH—Q   (I) 
provide pharmacological agents which are glucokinase activators and thus may be employed for the treatment of glucokinase mediated conditions. Accordingly, the compounds of formula (I) may be employed for prevention and treatment of impaired glucose tolerance, Type 2 diabetes and obesity.

The present invention relates to thiazole derivatives, pharmaceuticalcompositions containing them, and to methods of treating glucokinasemediated conditions, in particular, impaired glucose tolerance and Type2 diabetes, using such compounds.

Accordingly, the present invention provides compounds of the formula (I)R—NH—Q   (I)wherein

-   (i) Q is a-    radical in which R₁ and R₂ are independently hydrogen or halogen;    or    -   Q is a    -    radical in which R₃ is hydrogen, halogen, alkyl, cycloalkyl,        aryl, alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio,        arylthio, acyl, sulfonyl, alkylamino, cycloalkylamino,        arylamino, acylamino, sulfonamido or alkoxycarbonyl; Y is CH or        nitrogen; and    -   R is a radical of the formula    -    wherein    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₅ and R₆ are independently hydrogen, halogen, cyano, R₇,        —C(O)R₇ or —S(O)₂R₇    -   wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof; or-   (ii) Q is a-    radical in which R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl,    alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio,    acyl, sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino,    sulfonamido or alkoxycarbonyl; and    -   R is a radical of the formula    -    wherein    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₅ and R₆ are independently hydrogen, halogen, cyano, R₇,        —C(O)R₇ or —S(O)₂R₇    -   wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof; or-   (iii) Q is a-    radical in which R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl,    alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio,    acyl, sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino,    sulfonamido or alkoxycarbonyl; and    -   R is a radical of the formula    -    wherein    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₅ and R₆ are independently hydrogen, halogen, cyano, R₇, C(O)R₇        or —S(O)₂R₇    -   wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;-    provided that: (1) R₅ and R₆ are not halogen when n is zero; or (2)    R₅ is not —S(O)₂R₇, wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which m is    zero, W is a bond and R₁₀ is C₁₋₃alkyl when n is zero;    or an optical isomer thereof; or a pharmaceutically acceptable salt    thereof; or-   (iv) Q is a-    radical, wherein R₁ and R₂ are independently hydrogen or halogen;    and    -   R is a radical of the formula    -    wherein    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₁₂ and R₁₃ are independently hydrogen, halogen, cyano, R₁₄,        —C(O)R₁₄, or —S(O)₂R₁₄    -   wherein        -   R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₅ is cycloalkyl, aryl or heterocyclyl; or R₁₅ and R₁₁,                combined, are alkylene which together with the nitrogen                atom to which they are attached form a 5- to 7-membered                ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;-    provided that (1) R₁₂ and R₁₃ both are not hydrogen, halogen, cyano    or combinations thereof; (2) R₁₂ is not —S(O)₂R₁₄, wherein R₁₄ is    —(CR₈R₉)_(m)—W—R₁₅ in which m is zero and W is a bond when n is    zero; (3) R₁₂ is not —S(O)₂R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in    which R₈ and R₉ are hydrogen, m is 1 and W is a bond when n is    zero; (4) R₁₂ is not R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which    m is zero and W is O when n is zero; or (5) R₁₂ is not R₁₄, wherein    R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which m is zero and W is a bond when n    is zero;    or an optical isomer thereof; or a pharmaceutically acceptable salt    thereof.

The compounds of the present invention provide pharmacological agentswhich are glucokinase activators and, thus, may be employed for thetreatment of glucokinase mediated conditions. Accordingly, the compoundsof formula (I) may be employed for prevention and treatment of impairedglucose tolerance, Type 2 diabetes and obesity.

Listed below are definitions of various terms used to describe thecompounds of the present invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup, e.g., wherein an attachment point of a certain group is limitedto a specific atom within that group, the point of attachment is definedby an arrow at the specific atom.

The term “optionally substituted alkyl” refers to unsubstituted orsubstituted straight- or branched-chain hydrocarbon groups having 1-20carbon atoms, preferably 1-10 carbon atoms. Exemplary unsubstitutedalkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl andthe like. Substituted alkyl groups include, but are not limited to,alkyl groups substituted by one or more such as 2 or 3 of the followinggroups: halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy,alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl,thiol, alkylthio, alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro,cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy,guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl,thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl andthe like.

The term “lower alkyl” refers to those optionally substituted alkylgroups as described above having 1-7, preferably 2-4 carbon atoms.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkenyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon doublebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkynyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon triplebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkylene” refers to a straight-chain bridge of 4-6 carbonatoms connected by single bonds, e.g., —(CH₂)_(x)—, wherein x is 4-6,which may be interrupted with one or more heteroatoms selected from O,S, S(O), S(O)₂ or NR, wherein R may be hydrogen, alkyl, cycloalkyl,aryl, acyl, carbamoyl, sulfonyl, sulfamoyl, alkoxycarbonyl,aryloxycarbonyl or aralkoxycarbonyl, or the alkylene may be substitutedwith one or more substituents selected from alkyl, cycloalkyl, oxo,halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like.

The term “cycloalkyl” refers to optionally substituted monocyclic,bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each ofwhich may contain one or more carbon to carbon double bonds, or thecycloalkyl may be substituted by one or more substituents, such asalkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl,alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy,alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and thelike.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

The term “alkoxy” refers to alkyl-O-.

The term “alkanoyl” refers to alkyl-C(O)-.

The term “alkanoyloxy” refers to alkyl-C(O)—O-.

The terms “alkylamino” and “dialkylamino” refer to alkyl-NH- and(alkyl)₂N-, respectively,

The term “alkanoylamino” refers to alkyl-C(O)—NH-.

The term “alkylthio” refers to alkyl-S-.

The term “trialkylsilyl” refers to (alkyl)₃Si-.

The term “trialkylsilyloxy” refers to (alkyl)₃SiO-.

The term “alkylthiono” refers to alkyl-S(O)-.

The term “alkylsulfonyl” refers to alkyl-S(O)₂-.

The term “alkoxycarbonyl” refers to alkyl-O—C(O)-.

The term “alkoxycarbonyloxy” refers to alkyl-O—C(O)O-.

The term “carbamoyl” refers to H₂NC(O)-, alkyl-NHC(O)-, (alkyl)₂NC(O)-,aryl-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-,alkyl(heteroaryl)-NC(O)-, aralkyl-NHC(O)-, alkyl(aralkyl)-NC(O)- and thelike.

The term “sulfamoyl” refers to H₂NS(O)₂-, alkyl-NHS(O)₂-,(alkyl)₂NS(O)₂-, aryl-NHS(O)₂-, alkyl(aryl)-NS(O)₂-, (aryl)₂NS(O)₂-,heteroaryl-NHS(O)₂-, aralkyl-NHS(O)₂-, heteroaralkyl-NHS(O)₂- and thelike.

The term “sulfonamido” refers to alkyl-S(O)₂—NH-, aryl-S(O)₂NH-,aralkyl-S(O)₂—NH-, heteroaryl-S(O)₂—NH-, heteroaralkyl-S(O)₂—NH-,alkyl-S(O)₂N(alkyl)-, aryl-S(O)₂N(alkyl)-, aralkyl-S(O)₂N(alkyl)-,heteroaryl-S(O)₂-N(alkyl)-, heteroaralkyl-S(O)₂-N(alkyl)- and the like.

The term “sulfonyl” refers to alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-12 carbon atoms in the ring portion, such as phenyl,biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionallybe substituted by 1-4 substituents, such as optionally substitutedalkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl,alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio,arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono,sulfonyl, sulfonamido, heterocyclyl and the like.

The term “monocyclic aryl” refers to optionally substituted phenyl asdescribed under aryl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “aralkanoyl” refers to aralkyl-C(O)-.

The term “aralkylthio” refers to aralkyl-S-.

The term “aralkoxy” refers to an aryl group bonded directly through analkoxy group.

The term “arylsulfonyl” refers to aryl-S(O)₂-.

The term “arylthio” refers to aryl-S-.

The term “aroyl” refers to aryl-C(O)-.

The term “aroyloxy” refers to aryl-C(O)—O-.

The term “aroylamino” refers to aryl-C(O)—NH-.

The term “aryloxycarbonyl” refers to aryl-O—C(O)-.

The term “heterocyclyl” or “heterocyclo” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to12-membered bicyclic or 10- to 15-membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The heterocyclic group may be attached at a heteroatom or acarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl,1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl,benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl),phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

The term “heterocyclyl” includes substituted heterocyclic groups.Substituted heterocyclic groups refer to heterocyclic groups substitutedwith 1, 2 or 3 substituents selected from the group consisting of thefollowing:

-   -   (a) alkyl;    -   (b) hydroxy (or protected hydroxy);    -   (c) halo;    -   (d) oxo, i.e., ═O;    -   (e) optionally substituted amino, alkylamino or dialkylamino;    -   (f) alkoxy;    -   (g) cycloalkyl;    -   (h) carboxy;    -   (i) heterocyclooxy;    -   (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;    -   (k) mercapto;    -   (l) nitro;    -   (m) cyano;    -   (n) sulfamoyl or sulfonamido;    -   (o) aryl;    -   (p) alkanoyloxy;    -   (q) aroyloxy;    -   (r) arylthio;    -   (s) aryloxy;    -   (t) alkylthio;    -   (u) formyl;    -   (v) carbamoyl;    -   (w) aralkyl; and    -   (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy,        amino, acylamino, alkylamino, dialkylamino or halo.

The term “heterocyclooxy” denotes a heterocyclic group bonded through anoxygen bridge.

The term “heterocycloalkyl” refers to nonaromatic heterocyclic groups asdescribed above.

The term “heteroaryl” refers to an aromatic heterocycle, e.g.,monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzofuryl and the like, optionally substituted by,e.g., lower alkyl, lower alkoxy or halo.

The term “heteroarylsulfonyl” refers to heteroaryl-S(O)₂-.

The term “heteroaroyl” refers to heteroaryl-C(O)-.

The term “heteroaroylamino” refers to heteroaryl-C(O)NH-.

The term “heteroaralkyl” refers to a heteroaryl group bonded through analkyl group.

The term “heteroaralkanoyl” refers to heteroaralkyl-C(O)-.

The term “heteroaralkanoylamino” refers to heteroaralkyl-C(O)NH-.

The term “acyl” refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl and the like.

The term “acylamino” refers to alkanoylamino, aroylamino,heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.

Pharmaceutically acceptable salts of the compounds of the presentinvention are salts formed with acids, namely acid addition salts, suchas of mineral acids, organic carboxylic acids and organic sulfonicacids, e.g., hydrochloric acid, methanesulfonic acid and maleic acid.

Similarly, pharmaceutically acceptable salts of the compounds of theinvention include salts formed with bases, namely cationic salts, suchas alkali and alkaline earth metal salts, e.g., sodium, lithium,potassium, calcium and magnesium, as well as ammonium salts, e.g.,ammonium, trimethylammonium, diethylammonium andtris(hydroxymethyl)methylammonium salts and salts with amino acidsprovided an acidic group constitutes part of the structure.

The present invention provides thiazole derivatives of formula (I),pharmaceutical compositions containing them, methods for preparing saidcompounds, and methods of treating glucokinase mediated conditions byadministration of a therapeutically effective amount of a compound ofthe present invention or a pharmaceutical composition thereof.

In one embodiment, the compounds of formula (I) have the formula

wherein

-   -   R₁ and R₂ are independently hydrogen or halogen;    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₅ and R₆ are independently hydrogen, halogen, cyano, R₇,        —C(O)R₇ or —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5 to 7-membered ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Preferred are the compounds of formula (Ia), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Other preferred compounds are the compounds of formula (Ia), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;    -   R₆ is hydrogen or halogen;    -   R₅ is —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁, is hydrogen or lower alkyl preferably hydrogen,                -   most preferably W is a bond;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;                or an optical isomer thereof; or a pharmaceutically                acceptable salt thereof.

In another embodiment, the compounds of formula (I) have the formula

wherein

-   -   R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl, alkoxy,        cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,        sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino,        sulfonamido or alkoxycarbonyl;    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₅ and R₆ are independently hydrogen, halogen, cyano, R₇,        —C(O)R₇ or —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are, independently, hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which R₁₁ is hydrogen or                lower alkyl;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5 to 7-membered ring;            -   m is zero or an integer from 1 to 5;        -   Y is CH or nitrogen;        -   n is zero or an integer of 1 or 2;            or an optical isomer thereof; or a pharmaceutically            acceptable salt thereof.

Preferred are the compounds of formula (Ib), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Other preferred compounds are the compounds of formula (Ib), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;    -   R₆ is hydrogen or halogen preferably hydrogen;    -   R₅ is —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁, in which                -   R₁₁ is hydrogen or lower alkyl,                -   most preferably W is a bond;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;                or an optical isomer thereof; or a pharmaceutically                acceptable salt thereof.

Yet in another embodiment, the compounds of formula (I) have the formula

wherein

-   -   R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl, alkoxy,        cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,        sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino,        sulfonamido or alkoxycarbonyl;    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₅ and R₆ are independently hydrogen, halogen, cyano, R₇,        —C(O)R₇ or —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are, independently, hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Preferred are the compounds of formula (Ic), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Other preferred compounds are the compounds of formula (Ic), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;    -   R₆ is hydrogen or halogen preferably hydrogen;    -   R₅ is —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl,                -   most preferably W is a bond;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;                or an optical isomer thereof; or a pharmaceutically                acceptable salt thereof.

Other preferred compounds are the preferred compounds of formula (Ic) asdescribed above, wherein R₃ is hydrogen or alkoxy.

Yet in another embodiment, the compounds of formula (I) have the formula

wherein

-   -   R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl, alkoxy,        cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,        sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino,        sulfonamido or alkoxycarbonyl;    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₅ and R₆ are independently hydrogen, halogen, cyano, R₇,        —C(O)R₇, or —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are, independently, hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;        provided that: (1) R₅ and R₆ are not halogen when n is zero;        or (2) R₅ is not —S(O)₂R₇, wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in        which m is zero, W is a bond and R₁₀ is C₁₋₃alkyl when n is        zero;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Preferred are the compounds of formula (Id), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Other preferred compounds are the compounds of formula (Id), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;    -   R₆ is hydrogen or halogen most preferably hydrogen;    -   R₅ is —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl,                -   most preferably W is a bond;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;                or an optical isomer thereof; or a pharmaceutically                acceptable salt thereof.

Yet in another embodiment, the compounds of formula (I) have the formula

wherein

-   -   R₁ and R₂ are independently hydrogen or halogen;    -   R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl;    -   R₁₂ and R₁₃ are independently hydrogen, halogen, cyano, R₁₄,        —C(O)R₁₄, or —S(O)₂R₁₄    -   wherein        -   R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which            -   R₈ and R₉ are, independently, hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl;            -   R₁₅ is cycloalkyl, aryl or heterocyclyl; or R₁₅ and R₁₁,                combined, are alkylene which together with the nitrogen                atom to which they are attached form a 5- to 7-membered                ring;            -   m is zero or an integer from 1 to 5;    -   n is zero or an integer of 1 or 2;        provided that: (1) R₁₂ and R₁₃ both are not hydrogen, halogen,        cyano or combinations thereof; (2) R₁₂ is not —S(O)₂R₁₄ wherein        R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which m is zero and W is a bond        when n is zero; (3) R₁₂ is not —S(O)₂R₁₄, wherein R₁₄ is        —(CR₈R₉)_(m)—W—R₁₅ in which R₈ and R₉ are hydrogen, m is 1 and W        is a bond when n is zero; (4) R₁₂ is not R₁₄, wherein R₁₄ is        —(CR₈R₉)_(m)—W—R₁₅ in which m is zero and W is O when n is zero;        or (5) R₁₂ is not R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in        which m is zero and W is a bond when n is zero;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Preferred are the compounds of formula (Ie), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;        or an optical isomer thereof; or a pharmaceutically acceptable        salt thereof.

Other preferred compounds are the compounds of formula (Ie), wherein

-   -   R₄ is cyclopentyl;    -   n is zero;    -   R₆ is hydrogen or halogen preferably hydrogen;    -   R₅ is —S(O)₂R₇ wherein        -   R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which            -   R₈ and R₉ are independently hydrogen or lower alkyl;            -   W is a bond, O, S or —NR₁₁ in which                -   R₁₁ is hydrogen or lower alkyl,                -   most preferably W is a bond;            -   R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or                heterocyclyl; or R₁₀ and R₁₁, combined, are alkylene                which together with the nitrogen atom to which they are                attached form a 5- to 7-membered ring;            -   m is zero or an integer from 1 to 5;                or an optical isomer thereof; or a pharmaceutically                acceptable salt thereof.

The compounds of the invention depending on the nature of thesubstituents, may possess one or more asymmetric centers. The resultingdiastereoisomers, optical isomers, i.e., enantiomers, and geometricisomers, and mixtures thereof, are encompassed by the instant invention.Preferred are the compounds of the present invention wherein thesubstituent at the carbon atom adjacent to the amide or sulfonamidegroup attains the R-configuration.

Compounds of formula (I) may be prepared by coupling amines of theformulaH₂N—Q′  (II),or acid addition salts thereof, wherein Q′ represents Q as definedherein above, or Q′ is a group convertible to Q, with a compound of theformulaR′—Lg₁   (III)wherein R′ represents R as defined herein above, or R′ is a groupconvertible to R, and Lg₁ is a leaving group, e.g., chloride, in thepresence of a base such as triethylamine (TEA), diisopropylethylamine(DIEA), N-methylmorpholine (NMM) or pyridine, and an organic solvent,such as dichloromethane (DCM), N,N-dimethylformamide (DMF), acetonotrileor tetrahydrofuran (THF). The reaction may be conducted at an ambienttemperature, preferably at a temperature ranging from about −4° C. toabout 30° C. Amines of formula (II) and compounds of formula (III) areeither commercially available or they may be prepared using methodsdescribed herein in the Examples, or modifications thereof, or usingmethods well-known in the art.

For example, as illustrated in Scheme 1, sulfonyl chlorides of formula(IIIa), wherein R₄, R₅, R₆ and n have meanings as defined herein may becoupled with amines of formula (IIa), wherein R₁ and R₂ are as definedherein, in the presence of base e.g., pyridine, to afford sulfonamidesof formula (IV). Sulfonamides of formula (IV) may then be treated with abase, such as sodium hydride, lithium diisopropylamide (LDA) or lithiumbis(trimethylsilyl)amide (LHMDS), preferably LDA, followed by analkylating agent of formula (V), wherein R₄ has a meaning as definedherein, and Lg₂ represents a leaving group, such as chloride, bromide oriodide, to afford compounds of formula (Ia). The alkylation step ispreferably conducted in a polar organic solvent, such as THF, DMF,N-methylpyrrolidone (NMP) or1,3dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or in a mixtureof solvents thereof.

Similarly, as illustrated in Scheme 2, acid chlorides of formula (IIIb),wherein R₄, R₅, R₆ and n have meanings as defined herein, may be coupledwith amines of formula (IIa), wherein R₁ and R₂ are as defined herein,in the presence of base, e.g., pyridine, to afford amides of formula(Ie). Acid chlorides of formula (IIIb) may be prepared as illustrated inScheme 2, or using methods well-known in the art. For example, esters offormula (VI), wherein R₁₆ is lower alkyl, preferably methyl or ethyl,may be treated with a base, such as sodium hydride, LDA or LHMDS,preferably LDA, followed by an alkylating agent of formula (V), whereinR₄ has a meaning as defined herein, and Lg₂ represents a leaving group,such as chloride, bromide or iodide, to afford compounds of formula(VII). The alkylation step is preferably conducted in a polar organicsolvent, such as THF, DMF, NMP or DMPU, or in a mixture of solventsthereof. Compounds of formula (VII) may then be hydrolyzed, e.g., in thepresence of an aqueous base such as sodium, lithium or potassiumhydroxide and an organic solvent such as THF or lower alcohol,preferably methanol or ethanol. The resulting carboxylic acids may thenbe treated with a chlorinating agent such as thionyl chloride or oxalylchloride to afford acid chlorides of formula (IIIb).

In addition to acid chlorides, other activated derivatives of carboxylicacids may be used, e.g., acid bromides and fluorides, mixed anhydrides,lower alkyl esters, and activated esters thereof, and adducts formedwith coupling agents, such as1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (EDCl),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and the like. Mixed anhydrides are preferably suchfrom pivalic acid, or lower alkyl hemiesters of carbonic acids, such asethyl or isobutyl analogs. Activated esters include, for example,succinimido, phthalimido or 4-nitrophenyl esters. Carboxylic acids maybe converted to their activated derivatives using methods describedherein, or modifications thereof, or using methods well-known in theart.

The processes described herein above may be conducted under inertatmosphere, preferably under nitrogen atmosphere.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl andhydroxyl groups are those that can be converted under mild conditionsinto free amino thiol, carboxyl and hydroxyl groups without themolecular framework being destroyed or other undesired side reactionstaking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, etc.), the structure and stability of the molecule of whichthe substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, NY (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, room temperature (RT) or elevated temperatures, preferablyat or near the boiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

The invention also relates to any novel starting materials,intermediates and processes for their manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, diastereomers, optical isomers (antipodes), racemates ormixtures thereof. The aforesaid possible isomers or mixtures thereof arewithin the purview of this invention.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or tractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, the thiazolyl moiety may beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Finally, compounds of the invention are either obtained in the freeform, as a salt thereof if salt forming groups are present or as prodrugderivatives thereof.

Compounds of the instant invention which contain acidic groups may beconverted into salts with pharmaceutically acceptable bases. Such saltsinclude alkali metal salts, like sodium, lithium and potassium salts;alkaline earth metal salts, like calcium and magnesium salts; ammoniumsalts with organic bases, e.g., trimethylamine salts, diethylaminesalts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine, lysineand the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also bemused for purification of the compounds obtained.

Compounds of the invention having basic groups, in particular, thethiazolyl moiety, can be converted into acid addition salts, especiallypharmaceutically acceptable salts. These are formed, e.g., withinorganic acids, such as mineral acids, e.g., sulfuric acid, phosphoricor hydrohalic acid, or with organic carboxylic acids, such as(C₁-C₄)-alkanecarboxylic acids which, e.g., are unsubstituted orsubstituted by halogen, e.g., acetic acid, such as saturated orunsaturated dicarboxylic acids, e.g., oxalic, succinic, maleic orfumaric acid, such as hydroxycarboxylic acids, e.g., glycolic, lactic,malic, tartaric or citric acid, such as amino acids, e.g., aspartic orglutamic acid, or with organic sulfonic acids, such as(C₁-C₄)-alkylsulfonic acids, e.g., methanesulfonic acid; or arylsulfonicacids which are unsubstituted or substituted (for example by halogen).Preferred are salts formed with hydrochloric acid, maleic acid andmethanesulfonic acid.

Prodrug derivatives of any compound of the invention are derivatives ofsaid compounds which following administration release the parentcompound in vivo via some chemical or physiological process, e.g., aprodrug on being brought to the physiological pH or through enzymeaction is converted to the parent compound. Exemplary prodrugderivatives are, e.g., esters of free carboxylic acids and S-acyl andO-acyl derivatives of thiols, alcohols or phenols, wherein acyl has ameaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester and the like conventionally used in the art.

In view of the close relationship between the free compounds, theprodrug derivatives and the compounds in the form of their salts,whenever a compound is referred to in this context, a prodrug derivativeand a corresponding salt is also intended, provided such is possible orappropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, to activate glucokinase, andfor the treatment of conditions associated with glucokinase activity.Such conditions include impaired glucose tolerance, Type 2 diabetes andobesity. The said pharmaceutical compositions comprise a therapeuticallyeffective amount of a pharmacologically active compound of the instantinvention, alone or in combination with one or more pharmaceuticallyacceptable carriers.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising atherapeutically effective amount thereof in conjunction or admixturewith excipients or carriers suitable for either enteral or parenteralapplication. Preferred are tablets and gelatin capsules comprising theactive ingredient together with diluents, e.g., lactose, dextrose,sucrose, mannitol, sorbitol, cellulose and/or glycine; lubricants, e.g.,silica, talcum, stearic acid, its magnesium or calcium salt and/orpolyethyleneglycol; for tablets also binders, e.g., magnesium aluminumsilicate, starch paste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone; and if desireddisintegrants, e.g., starches, agar, alginic acid or its sodium salt; oreffervescent mixtures; and/or absorbants; colorants; flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously preparedfrom fatty emulsions or suspensions. Said compositions may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpre-determined rate over a prolonged period of time, and means to securethe device to the skin.

The pharmaceutical formulations contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include insulin, insulin derivatives and mimetics; insulinsecretagogues, such as the sulfonylureas, e.g., Glipizide, glyburide andAmaryl; insulinotropic sulfonylurea receptor ligands, such asmeglitinides, e.g., nateglinide and repaglinide; PPARα and/or PPARγ(peroxisome proliferator-activated receptor) ligands such as MCC-555,MK767, L-165041, GW7282 or thiazolidinediones such as rosiglitazone,ploglitazone, troglitazone; insulin sensitizers, such as proteintyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; GSK3(glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052,SB-216763, NN-57-05441, NN-57-05445 or RXR ligands such as GW-0791,AGN-194204; sodium-dependent glucose cotransporter inhibitors, such asT-1095, glycogen phosphorylase A inhibitors, such as BAY R3401;biguanides, such as metformin; alpha-glucosidase inhibitors, such asacarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogs, such asExendin-4, and GLP-1 mimetics; DPPIV (dipeptidyl peptidase IV)inhibitors such as LAF237; hypolipidemic agents, such as3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors,e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin,mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin,rosuvastatin, fluindostatin and rivastatin, squalene synthase inhibitorsor FXR (farnesoid X receptor) and LXR (liver X receptor) ligands,cholestyramine, fibrates, nicotinic acid and aspirin,, anti-obesityagents, such as orlistat, anti-hypertensive agents, inotropic agents andhypolipidemic agents, e.g., loop diuretics, such as ethacrynic acid,furosemide and torsemide; angiotensin converting enzyme (ACE)inhibitors, such as benazepril, captopril, enalapril, fosinopril,lisinopril, moexipril, perinodopril, quinapril, ramipril andtrandolapril; inhibitors of the Na-K-ATPase membrane pump, such asdigoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors, suchas omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists,such as candesartan, eprosartan, irbesartan, losartan, telmisartan andvalsartan, in particular valsartan; β-adrenergic receptor blockers, suchas acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol,propranolol, sotalol and timolol; inotropic agents, such as digoxin,dobutamine and milrinone; calcium channel blockers, such as amlodipine,bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine,nisoldipine and verapamil. Other specific antidiabetic compounds aredescribed by Patel Mona (Expert Opin Investig Drugs. 2003 Apr;12(4):623-33), in the FIGS. 1 to 7, which are herein incorporated byreference. A compound of the present invention may be administeredeither simultaneously, before or after the other active ingredient,either separately by the same or different route of administration ortogether in the same pharmaceutical formulation.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

Thus in an additional aspect the present invention concerns apharmaceutical composition comprising a therapeutically effective amountof a compound of the-invention in combination with one or morepharmaceutically acceptable carriers.

In a further aspect the present invention concerns a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the invention in combination with a therapeutically effective amountof another therapeutic agent, preferably selected from antidiabetics,hypolipidemic agents, anti-obesity agents, anti-hypertensive agents orinotropic agents, most preferably from antidiabetics or hypolipidemicagents as described above.

A pharmaceutical composition as described above for use as a medicament.

Use of a pharmaceutical composition or combination as described abovefor the preparation of a medicament for the treatment of conditionsassociated with glucokinase activity preferably impaired glucosetolerance, Type 1 or Type 2 diabetes, insulin resistance, dyslipidemia,metabolic syndrome X and obesity preferably Type 2 diabetes, impairedglucose tolerance and obesity.

A pharmaceutical composition as described above for the treatment ofconditions associated with glucokinase activity preferably impairedglucose tolerance, Type 1 or Type 2 diabetes, insulin resistance,dyslipidemia, metabolic syndrome X and obesity.

A unit dosage for a mammal of about 50-70 kg may contain between about 1mg and 1000 mg, advantageously between about 5-500 mg of the activeingredient. The therapeutically effective dosage of a compound offormula (I) is dependent on the species of warm-blooded animal (mammal),the body weight, age and individual condition, on the form ofadministration and on the compound involved.

The compounds of the present invention are glucokinase activators, andthus may be employed for the treatment of conditions associated withglucokinase activity, as described herein, e.g., impaired glucosetolerance, Type 2 diabetes, insulin resistance, dyslipidemia, metabolicsyndrome X and obesity.

Thus, in an additional embodiment, the present invention relates to;

-   -   A compound of the invention for use as a medicament    -   The use of a compound of the invention for the preparation of a        pharmaceutical composition for the prevention and/or treatment        of conditions associated with glucokinase activity.    -   A pharmaceutical composition, for use in conditions associated        with glucokinase activity comprising a compound of formula I in        free form or pharmaceutically acceptable salt form in        association with a pharmaceutically acceptable diluent or        carrier therefore.    -   A method for the prevention and/or treatment of conditions        associated with glucokinase activity, which comprises        administering a therapeutically effective amount of a compound        of the invention.

In accordance with the foregoing the present invention provides in a yetfurther aspect:

-   -   A therapeutic combination, e.g. a kit, kit of parts e.g. for use        in any method as defined herein, comprising a compound of        formula I, in free form or in pharmaceutically acceptable salt        form, to be used concomitantly or in sequence with at least one        pharmaceutical composition comprising at least another        therapeutic agent, preferably selected from antidiabetics,        hypolipidemic agents, anti-obesity agents, anti-hypertensive        agents or inotropic agents. The kit may comprise instructions        for its administration.    -   A kit of parts comprising        -   (i) a pharmaceutical composition of the invention, (ii) a            pharmaceutical composition comprising a compound selected            from an antidiabetic, anti-obesity agent, anti-hypertensive            agent, inotropic agent or hypolipidemic agent, or a            pharmaceutically acceptable salt thereof, in the form of two            separate units of the components (i) to (ii).    -   A method as defined above comprising co-administration, e.g.        concomitantly or in sequence, of a therapeutically effective        amount of a compound of formula I in free form or in        pharmaceutically acceptable salt form, and a second drug        substance, said second drug substance being a antidiabetic,        anti-obesity agent, anti-hypertensive agent, inotropic agent or        hypolipidemic agent, e.g. as indicated above.

Preferably the compound of the invention is administered to a mammal inneed thereof.

Preferably the compound of the invention is used for the treatment of adisease which responds to activation of glucokinase activity.

Preferably the conditions associated with glucokinase activity areselected from impaired glucose tolerance, Type 1 or Type 2 diabetes,insulin resistance, dyslipidemia, metabolic syndrome X and obesity, mostpreferably Type 2 diabetes, impaired glucose tolerance and obesity.

A method or use according to the invention which comprises administeringsaid compound in combination with a therapeutically effective amount ofan antidiabetic agent, anti-obesity agent, anti-hypertensive agent,inotropic agent or hypolipidemic agent.

A method or use according to the invention which comprises administeringsaid compound in the form of a pharmaceutical composition as describedherein.

As used throughout the specification and in the claims, the term“treatment” embraces all the different forms or modes of treatment asknown to those of the pertinent art and in particular includespreventive, curative, delay of progression and palliative treatment.

The above-cited properties are demonstrable in vitro and in vivo testsusing advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. Said compounds can beapplied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo either enterally, parenterally, advantageouslyintravenously, e.g., as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻² molar and 10⁻⁹ molarconcentrations. A therapeutically effective amount in vivo may rangedepending on the route of administration, between about 0.1 mg/kg and1000 mg/kg, preferably between about 1 mg/kg and 100 mg/kg.

The activity of compounds according to the invention may be assessed bythe following methods or methods well-described in the art:

The glucokinase activation in vitro may be determined by measuring theactivation of recombinant GST-GK by a compound of the present inventionin the absence or the presence of GKRP, a 68,000 Da protein inhibitor ofGK. In these assays, formation of glucose-6-phosphate is coupleddirectly to the formation of thioNADH. GST-GK catalyzes the reaction ofglucose and Mg-ATP to produce glucose-6-phosphate and ADP.Glucose-6-phosphate dehydrogenase (G6PDH) reduces thionicotinamide(thioNAD) to thioNADH. The assay measures the formation of NADH at 405nM.

The basic GK assay components are as follows: 25 mM HEPES (pH 7.1), 25mM KCl, 2.5 mM MgCl₂, 1 mM ATP (Sigma A-5394), 1 mM DTT, 1 mM thioNAD(Sigma T-7375), 80 units/mL G6PDH (Sigma G-5885), 10 mM glucose and 8.7mg/mL GST-GK (110 nM). For assessing reversal of GK inhibition by GKRP,20 μM Fructose-1-phosphate (F-6-P) and 25 μg/mL of recombinant GKRP (370nM) are added to these assay components. F-1-P at 1 μM is used as acontrol in the GK/GKRP assay. F-1-P reverses inhibition of GST-GK byGKRP.

The assay is done in standard, 96-well, round-bottom plates and thetotal assay volume is 25 μL. Compounds are serially diluted into 100%DMSO and 0.5 μL of diluted compound in 100% DMSO is added to the assayplate. Assay reagents (24.5 μL) are added using a Zymark roboticplatform. Buffer, containing HEPES, MgCl₂, KCl, thioNAD, G6PDH, F-6-P,glucose, GKRP and GST-GK, are added (5 μL) using the Zymark 8-channelhand pipet. The reaction is then initiated by adding 19.5 μL of buffercontaining HEPES, MgCl₂, KCl, DOTT and ATP using the Zymark ReagentAddition Station/Reagent Addition Module. The plates are then deliveredvia the Zymark XP arm to a Thermomax plate reader and read kineticallyover three min at 405 nM at RT. Units are expressed as milli-opticaldensity per minute (mOD/min).

The glucokinase activation in rat hepatocytes may be determined asfollows:

Hepatocytes are isolated by collagenase perfusion of the livers ofovernight-fasted male Harlen Sprague-Dawley rats (Charles RiverLaboratories, Raleigh, N.C.) as previously described (see Berry et al.,J. Cell Biol., Vol. 43, pp. 506-520 (1969)). The cells are washed threetimes each with 100 mL of glucose-free Dulbecco's Modified Eagle medium(DMEM, Gibco BRL) containing 5% fetal bovine serum (FBS) and thensuspended in glucose-free DMEM/5% FBS. Cells are plated in collagencoated 24-well plates (Becton Dickinson) at a density of 3×10⁵cells/well in 1 mL of William's Medium E (Sigma) supplemented with 5%FBS, and incubated at 37° C. in 5% /CO₂/95% air. After cell attachment(˜4 h), the medium is replaced with serum-free DMEM containing 5 mMglucose and 10 nM dexamethasone (Sigma), and cells are cultured furtherfor 16-20 h prior to use.

The rate of glucose phosphorylation is determined by the release of ³H₂Ofrom [2-³H]glucose. The medium from the cultured hepatocytes is removed,and the cells are pre-incubated in 150 μL of fresh serum-free DMEMcontaining 5 mM glucose and compound (1, 10 and 30 μM) or DMSO for 3 hat 37° C. The final concentration of DMSO is 0.2%. The medium is thenremoved and 150 μL of a fresh mixture of DMEM/5 mM glucose containingcompound or DMSO, and 1 μCi of [2-³H]glucose (NEN) is added. As apositive control for stimulation of glucose phosphorylation, cells arepre-incubated in serum-free DMEM/5 mM glucose medium containing DMSO for3 h and then are incubated for 1 h in labeled glucose medium containing0.5 mM fructose/DMSO (precursor of F-1-P, AnalaR® from BDH). Allconditions are tested in quadruplicate where one well per plate received200 μL of the appropriate medium plus labeled glucose (instead of 150μL) of which 50 μL is immediately removed and placed in a 1.2 mLmicrofuge tube (Costar) containing 10 μL of 1 N HCl. This sample is usedas a 0-minute time point for determining background ³H₂O release(exchange values). Following the addition of the labeled glucose media,hepatocytes are incubated at 37° C. on a slow moving rocker for 1 h.

On termination of the incubation, 50 μL of the culture medium iscollected into microfuge tubes containing 10 μL of 1 N HCl, anddetermination of ³H₂O. The tubes are left uncapped and each is placedinside a 20 mL glass scintillation vial (Wheaton) containing 1.5 mL ofdeionized water. The vials are capped tightly and incubated at 37° C. ina dry incubator for 2 days (³H₂O from the reaction mixture willequilibrate with the water in the vial). A standard curve is generatedusing [³H]H₂O (NEN) to correct for exchange. 50 μL aliquots of serialdilutions of the labeled water are added to 10 μL of 1 N HCl andexchange is performed as described for the samples (typically,approximately 90% exchange is observed). The microfuge tubes are thenremoved from the vials carefully to minimize the removal of any waterfrom the vial and 18 mL of scintillation cocktail (Ready Safe, BeckmanCoulter) is then added to each vial. The ³H-label recovered from[2-³H]glucose in the water is determined using a Beckman Model LS500scintillation counter and the counts (minus the 0-time point) arecorrected for recovery of ³H₂O. The amount of glucose de-tritiated innanomoles/h per 10⁶ cells is calculated, and the results are expressedas percent increase over the DMSO control.

Our compounds exhibit high affinity, selectivity, improved potency aswell as good oral bioavailability, pharmacokinetic profile and safety.

Our compounds are particularly useful for treating diabetes or IGTwithout a serious risk of hypoglycemia, and have the potential todecrease the risk of cardiovascular diseases in patients especially inindividuals with type 2 diabetes or IGT. Thus, our compounds would beappropriate to use for long-term treatments, particularly for use indiabetes, in diabetes prevention such as in IGT patients. Our compoundsexhibit a stronger control of the fasting plasma glucose level,postprandial plasma glucose level, serum triglycerides level,haemoglobin A1c level without a serious risk of hypoglycemia or fat massincrease. Furthermore, they exhibit long duration of action, long-termtolerability, safety and lower glycaemic peaks as well as a better dailycontrol of the plasma insulin level. Our compounds have the advantage toaugment hepatic glucose metabolism, glucose usage in the liver andglucose-induced insulin secretion from pancreatic islets with a higherefficacy which should provide greater efficacy as a monotherapy.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, all evaporations are performed under reduced pressure,preferably between about 50 mmHg and 100 mmHg. The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis, melting point (m.p.) andspectroscopic characteristics, e.g., MS, IR and NMR. Abbreviations usedare those conventional in the art.

EXAMPLE 13-Cyclopentyl-2-[4-(2-phenyl-ethanesulfonyl)-phenyl]-N-thiazol-2-yl-propionamide

A. 3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid methylester

To a solution of diispropylamine (25 mmol, 3.6 mL) in 24 mL of THF and7.5 mL of methidathion (DMTP) at −78° C. is added n-BuLi (25 mmol, 10mL, 2.5 M in hexanes) and the mixture stirred for 15 min.4-Methylsulfonylphenylacetic acid methyl ester (24 mmol, 5.47 g) in 24mL of THF and 7.5 mL of DMTP is then added dropwise over 30 min and thereaction is stirred for 90 min further. Cyclopentylmethyliodide (28.9mmol, 6.08 g) in 10 mL of THF is then added dropwise and the reaction isstirred for 1 h at −78° C. before allowing to warm to RT. After 12 h,the reaction is quenched with water, evaporated and then partitionedbetween ethyl acetate (EtOAc) and brine, and the organic solution isdried and evaporated to afford an oil. The crude material ischromatographed on silica (eluent: 5%→25% EtOAc in hexanes) to afford3cyclopentyl-2-(4methanesulfonyl-phenyl)-propionic acid methyl ester.

B. 3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid

The title A compound,3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester(17.4 mmol, 5.4 g) is saponified under standard conditions using aqueous1 N aqueous NaOH in methanol (MeOH) with warming to 60° C. in an oilbath. The solvent is removed by evaporation and the aqueous residue isacidified with aqueous 6 N aqueous HCl. The resulting solid is collectedby filtration and washed with water and dried under vacuum to afford3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid as a whitesolid.

C.3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide

The title B compound,3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (3.44 mmol,1.02 g) is suspended in thionyl chloride (5 mL) with a catalytic amountof DMF and stirred for 12 h. The mixture is evaporated and then dilutedwith toluene and re-evaporated to afford an oil which is diluted with 4mL of DCM and added to 2-aminothiazole (3.8 mmol, 0.4 g) in 10 mL ofpyridine at 0° C. and then stirred for 12 h while warming to RT. Thereaction mixture is evaporated, diluted with EtOAc and 0.1 N HCl and theorganic solution is washed with brine, dried and evaporated to an oil.Chromatography on silica (eluent: 5%→25% EtOAc in hexanes) affords3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide:¹H NMR δ 11.7 (s, 1H), 7.86 (d, J=8, 2H), 7.55 (d, J=3.5, 1H), 7.53 (d,J=8, 2H), 7.10 (d, J=3.5, 1H), 3.81 (t, J=7.5, 1H), 3.03 (s, 3H),1.1-2.2 (m, 11H).

D.3-Cyclopentyl-2-[4-(2-phenyl-ethanesulfonyl)-phenyl]-N-thiazol-2-yl-propionamide

The title C compound,3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide(0.58 mmol, 220 mg) is dissolved in 15 mL of THF and cooled to −78° C.LHMDS (1.2 mmol, 1.2 mL of 1.0 M solution) is added and the mixture isstirred to 1 h at −78° C. Benzyl bromide (0.6 mmol, 103 mg) is added andthe mixture stirred at −78° C. for 2 h further. The reaction mixture isquenched with aqueous saturated ammonium chloride, the solvent isevaporated and the residue is partitioned between EtOAc and brine. Theorganic solution is dried and evaporated to an oil. Chromatography onsilica (eluent: 35% EtOAc in hexanes) affords3-cyclopentyl-2-[4-(2-phenyl-ethanesulfonyl)-phenyl]-N-thiazol-2-yl-propionamide:¹H NMR δ 11.8 (s, 1H), 7.86 (d, J=8, 2H), 7.55 (m, 3H), 7.05-7.32 (m,6H) 3.8 (t, J=7.5, 1H), 3.33 (m, 2H), 3.05 (m, 2H), 2.29 (m, 1H),1.0-1.9 (m, 8H); e/z (ES) 469 (M+1, 100%).

EXAMPLE 2 2-Cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethanesulfonic acidthiazol-2-ylamide

A. (4-Methanesulfonyl-phenyl)-methanesulfonic acid, sodium salt

To a solution of 1-chloromethyl-4-methanesulfonyl-benzene (48.8 mmol, 10g) in 180 mL of water and 20 mL of DMF is added Na2SO₃ (0.116 mmol, 14.6g) and the mixture stirred at 40° C. for 12 h. The reaction isevaporated and the resulting solid is triturated with ethanol to affordcrude (4-methanesulfonyl-phenyl)-methanesulfonic acid, sodium salt whichis used as such in the next step.

B. (4-Methanesulfonyl-phenyl)-methanesulfonyl chloride

To the title A compound, (4-methanesulfonyl-phenyl)-methanesulfonicacid, sodium salt is added PCl₅ (10 g) in 200 mL of chloroform and themixture is stirred for 48 h. The solids are filtered off, the chloroformis removed by evaporation, and the residue is triturated with hexanes,and the solids are collected by filtration to afford(4-methanesulfonyl-phenyl)-methanesulfonyl chloride.

C. C-(4-Methanesulfonyl-phenyl)-N-thiazol-2-yl-methanesulfonamide

To the solution of the title B compound,(4-methanesulfonyl-phenyl)-methanesulfonyl chloride (1.86 mmol, 0.5 g)in 5 mL of pyridine is added 2-aminothiazole (2.5 mmol, 0.25 g) and themixture is stirred for 48 h. The reaction mixture is quenched withaqueous 1 N HCl and the product is taken up in EtOAc, dried andconcentrated to affordC-(4-methane-sulfonyl-phenyl)-N-thiazol-2-yl-methanesulfonamide.

D. 2-Cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethanesulfonic acidthiazol-2-ylamide

To a solution of diisopropylamine (1.0 mmol, 0.10 g) in 7 mL of THF and3 mL of DMPU at 0° C. is added n-BuLi (0.61 mL, 2.5 M in hexane) and thereaction mixture is stirred for 15 min, then cooled to −78° C. The titleC compound,C-(4-methane-sulfonyl-phenyl)-N-thiazol-2-yl-methanesulfonamide (0.693mmol, 0.23 g) is added and the reaction mixture is allowed to warm to 0°C. After 1 h, the reaction is recooled to −78° C.,cyclopentylmethyliodide (0.72 mmol, 0.15 g) is added and the reaction isallowed to warm to RT over 3 h. The reaction mixture is poured intoaqueous 1 N HCl, and the product is taken up in EtOAc, dried andevaporated to afford an orange oil. Chromatography on silica affords2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethanesulfonic acidthiazol-2-ylamide: ¹H NMR δ 11.6 (br s, 1H), 7.84 (d, J=8, 2H), 7.58 (d,J=8, 2H), 6.67 (d, J=4.5, 1H), 6.39 (d, J=4.5, 1H); 4.27 (m, 1H), 3.03(s, 3H), 2.04-2.2 (m, 1H), 1.12-1.61 (m, 10H); e/z (ES) 415 (M+1, 100%).

EXAMPLE 33-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methoxy-thiazolo[5,4b]pyridin-2-yl)-propionamide

A. 5-Methoxy-thiazolo[5,4-b]pyridin-2-ylamine

A solution of 6-methoxy-pyridin-3-ylamine (40.3 mmol, 5.0 g) in 10 mL ofacetic acid is added slowly to a solution of potassium thiocyanate (205mmol, 20 g) in 100 mL of acetic acid at 0° C. followed by a solution ofbromine (48.8 mmol, 2.5 mL) in 5 mL of acetic acid. The reaction isstirred for 2 h at 0° C. and then allowed to warm to RT. The resultingsolid is collected by filtration and washed with acetic acid, thenpartitioned between EtOAc and saturated aqueous NaHCO₃. The insolublematerial is removed by filtration and the organic layer is dried andevaporated to afford 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a tansolid.

B.3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methoxythiazolo[5,4b]pyridin-2-yl)-propionamide

To a solution of the title A compound,5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (1.22 mmol, 222 mg) in 3 mLof pyridine at 0° C. is added3-cyclopentyl-2-(4-methansulfonyl-phenyl)-propionyl chloride (1.02 mmol,prepared as described for the preparation of the title C compound inExample 1). The reaction is allowed to warm to RT over 12 h, thenevaporated and the residue is partitioned between MTBE and aqueous 0.1 NHCl. The organic solution is washed with water, saturated aqueous NaHCO₃and brine, dried and evaporated to an oil. Chromatography over silicaaffords3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide;¹H NMR δ 9.7 (s, 1H), 7.85 (m, 3H), 7.38 (d, J=8, 2H), 6.83 (d, J=8,1H), 4.05 (s, 3H), 3.63 (t, J=7.5, 1H); 3.09 (s, 3H), 2.2 (m, 1H),1.1-1.9 (m, 10H); e/z (ES) 460 (M+1, 100%).

1. A compound of the formulaR—NH—Q   (I) wherein (i) Q is a

 radical in which R₁ and R₂ are independently hydrogen or halogen; or Qis a

 radical in which R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl,alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino, sulfonamidoor alkoxycarbonyl; Y is CH or nitrogen; and R is a radical of theformula

 wherein R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl; R₅ andR₆ are independently hydrogen, halogen, cyano, R₇, —C(O)R₇ or —S(O)₂R₇wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which R₈ and R₉ are independentlyhydrogen or lower alkyl; W is a bond, O, S or —NR₁₁ in which R₁₁ ishydrogen or lower alkyl; R₁₀ is hydrogen, alkyl, cycloalkyl, aryl orheterocyclyl; or R₁₀ and R₁₁, combined, are alkylene which together withthe nitrogen atom to which they are attached form a 5- to 7-memberedring; m is zero or an integer from 1 to 5; n is zero or an integer of 1or 2; or an optical isomer thereof; or a pharmaceutically acceptablesalt thereof; or (ii) Q is a

 radical in which R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl,alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino, sulfonamidoor alkoxycarbonyl; and R is a radical of the formula

 wherein R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl; R₅ andR₆ are independently hydrogen, halogen, cyano, R₇, —C(O)R₇ or —S(O)₂R₇wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which R₈ and R₉ are independentlyhydrogen or lower alkyl; W is a bond, O, S or —NR₁₁ in which R₁₁ ishydrogen or lower alkyl; R₁₀ is hydrogen, alkyl, cycloalkyl, aryl orheterocyclyl; or R₁₀ and R₁₁, combined, are alkylene which together withthe nitrogen atom to which they are attached form a 5- to 7-memberedring; m is zero or an integer from 1 to 5; n is zero or an integer of 1or 2; or an optical isomer thereof; or a pharmaceutically acceptablesalt thereof; or (iii) Q is a

 radical in which R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl,alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino, sulfonamidoor alkoxycarbonyl; and R is a radical of the formula

 wherein R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl; R₅ andR₆ are independently hydrogen, halogen, cyano, R₇, —C(O)R₇ or —S(O)₂R₇wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which R₈ and R₉ are independentlyhydrogen or lower alkyl; W is a bond, O, S or —NR₁₁ in which R₁₁ ishydrogen or lower alkyl; R₁₀ is hydrogen, alkyl, cycloalkyl, aryl orheterocyclyl; or R₁₀ and R₁₁, combined, are alkylene which together withthe nitrogen atom to which they are attached form a 5- to 7-memberedring; m is zero or an integer from 1 to 5; n is zero or an integer of 1or 2;  provided that: (1) R₅ and R₆ are not halogen when n is zero; or(2) R₅ is not —S(O)₂R₇, wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which m iszero, W is a bond and R₁₀ is C₁₋₃alkyl when n is zero; or an opticalisomer thereof; or a pharmaceutically acceptable salt thereof; or (iv) Qis a

 radical, wherein R₁ and R₂ are independently hydrogen or halogen; and Ris a radical of the formula

 wherein R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl; R₁₂and R₁₃ are independently hydrogen, halogen, cyano, R₁₄, —C(O)R₁₄, or—S(O)₂R₁₄ wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which R₈ and R₉ areindependently hydrogen or lower alkyl; W is a bond, O, S or —NR₁₁ inwhich R₁₁ is hydrogen or lower alkyl; R₁₅ is cycloalkyl, aryl orheterocyclyl; or R₁₅ and R₁₁, combined, are alkylene which together withthe nitrogen atom to which they are attached form a 5- to 7-memberedring; m is zero or an integer from 1 to 5; n is zero or an integer of 1or 2;  provided that: (1) R₁₂ and R₁₃ both are not hydrogen, halogen,cyano or combinations thereof; (2) R₁₂ is not —S(O)₂R₁₄, wherein R₁₄ is—(CR₈R₉)_(m)—W—R₁₅ in which m is zero and W is a bond when n is zero;(3) R₁₂ is not —S(O)₂R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which R₈and R₉ are hydrogen, m is 1 and W is a bond when n is zero; (4) R₁₂ isnot R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which m is zero and W is 0when n is zero; or (5) R₁₂ is not R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅in which m is zero and W is a bond when n is zero; or an optical isomerthereof; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 of the formula

wherein R₁ and R₂ are independently hydrogen or halogen; R₄ isC₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl; R₅ and R₆ areindependently hydrogen, halogen, cyano, R₇, —C(O)R₇ or —S(O)₂R₇ whereinR₇ is —(CR₈R₉)_(m)—W—R₁₀ in which R₈ and R₉ are independently hydrogenor lower alkyl; W is a bond, O, S or —NR₁₁ in which R₁₁ is hydrogen orlower alkyl; R₁₀ is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl;or R₁₀ and R₁₁, combined, are alkylene which together with the nitrogenatom to which they are attached form a 5- to 7-membered ring; m is zeroor an integer from 1 to 5; n is zero or an integer of 1 or 2; or anoptical isomer thereof; or a pharmaceutically acceptable salt therof. 3.A compound according to claim 2, wherein R₄ is cyclopentyl; n is zero;or an optical isomer thereof; or a pharmaceutically acceptable saltthereof.
 4. A compound according to claim 1 of the formula

wherein R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl, alkoxy,cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino, sulfonamidoor alkoxycarbonyl; R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl orC₅₋₇heterocycloalkyl; R₅ and R₆ are independently hydrogen, halogen,cyano, R₇, —C(O)R₇ or —S(O)₂R₇ wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in whichR₈ and R₉ are, independently, hydrogen or lower alkyl; W is a bond, O, Sor —NR₁₁ in which R₁₁ is hydrogen or lower alkyl; R₁₀ is hydrogen,alkyl, cycloalkyl, aryl or heterocyclyl; or R₁₀ and R₁₁, combined, arealkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; m is zero or an integer from 1 to5; Y is CH or nitrogen; n is zero or an integer of 1 or 2; or an opticalisomer thereof; or a pharmaceutically acceptable salt thereof.
 5. Acompound according to claim 4, wherein R₄ is cyclopentyl; n is zero; oran optical isomer thereof; or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 1 of the formula

wherein R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl, alkoxy,cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino, sulfonamidoor alkoxycarbonyl; R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl orC₅₋₇heterocycloalkyl; R₅ and R₆ are independently hydrogen, halogen,cyano, R₇, —C(O)R₇ or —S(O)₂R₇ wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in whichR₈ and R₉ are, independently, hydrogen or lower alkyl; W is a bond, O, Sor —NR₁₁ in which R₁₁ is hydrogen or lower alkyl; R₁₀ is hydrogen,alkyl, cycloalkyl, aryl or heterocyclyl; or R₁₀ and R₁₁, combined, arealkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; m is zero or an integer from 1 to5; n is zero or an integer of 1 or 2; or an optical isomer thereof; or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 6, wherein R₄ is cyclopentyl; n is zero; or an optical isomerthereof; or a pharmaceutically acceptable salt thereof.
 8. A compoundaccording to claim 1 of the formula

wherein R₃ is hydrogen, halogen, alkyl, cycloalkyl, aryl, alkoxy,cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, acyl,sulfonyl, alkylamino, cycloalkylamino, arylamino, acylamino, sulfonamidoor alkoxycarbonyl; R₄ is C₂₋₄alkyl, C₃₋₇cycloalkyl orC₅₋₇heterocycloalkyl; R₅ and R₆ are independently hydrogen, halogen,cyano, R₇, —C(O)R₇, or —S(O)₂R₇ wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ inwhich R₈ and R₉ are, independently, hydrogen or lower alkyl; W is abond, O, S or —NR₁, in which R₁₁ is hydrogen or lower alkyl; R₁₀ ishydrogen, alkyl, cycloalkyl, aryl or heterocyclyl; or R₁₀ and R₁₁,combined, are alkylene which together with the nitrogen atom to whichthey are attached form a 5- to 7-membered ring; m is zero or an integerfrom 1 to 5; n is zero or an integer of 1 or 2; provided that: (1) R₅and R₆ are not halogen when n is zero; or (2) R₅ is not —S(O)₂R₇,wherein R₇ is —(CR₈R₉)_(m)—W—R₁₀ in which m is zero, W is a bond and R₁₀is C₁₋₃alkyl when n is zero; or an optical isomer thereof; or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 8, wherein R₄ is cyclopentyl; n is zero; or an optical isomerthereof; or a pharmaceutically acceptable salt thereof.
 10. A compoundaccording to claim 1 of the formula

wherein R₁ and R₂ are independently hydrogen or halogen; R₄ isC₂₋₄alkyl, C₃₋₇cycloalkyl or C₅₋₇heterocycloalkyl; R₁₂ and R₁₃ areindependently hydrogen, halogen, cyano, R₁₄, —C(O)R₁₄, or —S(O)₂R₁₄wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which R₈ and R₉ are, independently,hydrogen or lower alkyl; W is a bond, O, S or —NR₁₁ in which R₁₁ ishydrogen or lower alkyl; R₁₅ is cycloalkyl, aryl or heterocyclyl; or R₁₅and R₁₁, combined, are alkylene which together with the nitrogen atom towhich they are attached form a 5- to 7-membered ring; m is zero or aninteger from 1 to 5; n is zero or an integer of 1 or 2; provided that:(1) R₁₂ and R₁₃ both are not hydrogen, halogen, cyano or combinationsthereof; (2) R₁₂ is not —S(O)₂R₁₄ wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ inwhich m is zero and W is a bond when n is zero; (3) R₁₂ is not—S(O)₂R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which R₈ and R₉ arehydrogen, m is 1 and W is a bond when n is zero; (4) R₁₂ is not R₁₄,wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ in which m is zero and W is O when nis zero; or (5) R₁₂ is not R₁₄, wherein R₁₄ is —(CR₈R₉)_(m)—W—R₁₅ inwhich m is zero and W is a bond when n is zero; or an optical isomerthereof; or a pharmaceutically acceptable salt thereof.
 11. A compoundaccording to claim 10, wherein R₄ is cyclopentyl; n is zero; or anoptical isomer thereof; or a pharmaceutically acceptable salt thereof.12. A method for the activation of glucokinase activity in mammals whichmethod comprises administering to a mammal in need thereof atherapeutically effective amount of a compound of claim
 1. 13. A methodfor the prevention and/or treatment of conditions associated withglucokinase activity in mammals which method comprises administering toa mammal in need thereof a therapeutically effective amount of acompound of claim
 1. 14. The method according to claim 13, which methodcomprises administering said compound in combination with atherapeutically effective amount of insulin, insulin derivative ormimetic; insulin secretagogue; insulinotropic sulfonylurea receptorligand; PPAR ligand; insulin sensitizer; biguanide; alpha-glucosidaseinhibitors; GLP-1, GLP-1 analog or mimetic; DPPIV inhibitor; PTP-1Binhibitor; HMG-CoA reductase inhibitor; squalene synthase inhibitor; FXRor LXR ligand; cholestyramine; fibrates; nicotinic acid or aspirin. 15.A method for the treatment of impaired glucose tolerance, Type 2diabetes and obesity which method comprises administering to a mammal inneed thereof a therapeutically effective amount of a compound ofclaim
 1. 16. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 in combination with one ormore pharmaceutically acceptable carriers.
 17. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 in combination with a therapeutically effective amount ofinsulin, insulin derivative or mimetic; insulin secretagogue;insulinotropic sulfonylurea receptor ligand; PPAR ligand; insulinsensitizer; biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analogor mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor; squalenesynthase inhibitor; FXR or LXR ligand; cholestyramine; fibrates;nicotinic acid; or aspirin.
 18. A pharmaceutical composition accordingto claim 16 or 17 for the treatment of impaired glucose tolerance, Type2 diabetes and obesity. 19-23. (canceled)
 24. A pharmaceuticalcomposition according to claim 17 for the treatment of impaired glucosetolerance, Type 2 diabetes and obesity.